The invention relates to freeze-dried compositions comprising                a) at least one polymer based on polyacrylic acids and salts thereof,        b) at least one natural polymer,        c) optionally at least one further polymer which differs from a) and b) and        d) optionally one or more active compounds and/or auxiliary substances.        
The invention furthermore relates to a process for the preparation of such freeze-dried compositions, the combination of such freeze-dried compositions in kit-of-parts arrangements together with aqueous solutions and the use of the freeze-dried compositions and of the kit-of-parts combinations for cosmetic and pharmaceutical use, in particular for use as a cosmetic mask or as a wound covering and for the preparation of pharmaceutical agents for treatment of dermal wounds, such as, in particular, chronic wounds, ulcus cruris or decubitus.
Various agents for cosmetic and therapeutic treatment of the human and/or animal body are known in the most diverse presentation and administration forms. Compositions and agents in the form of solid, dry formulations configured as sponges, sheets, matrices, coverings, pads, leaves, masks, layers or other planar forms as well as those in the form of shaped bodies of large format play an important role here, in particular in the pharmaceutical field of wound care, but increasingly also in the field of cosmetic uses. Such embodiments are particularly suitable for external and areal treatment and care of the skin, and in particular for the care of areal skin injuries or wounds. Depending on the desired treatment aim or chosen field of use of such coverings, particular, sometimes very specific material and functional requirements are imposed on such compositions, in particular on their chemical composition and their physical or biochemical mode of action and function. Specifically in the case of external dermal treatment, the complex biochemical interactions and modes of function with the organ “skin” are to be remembered.
In this context, the care and protection of the skin, e.g. by a cosmetic treatment, and the restoration, curing or alleviation of dysfunctions or injuries of the skin by a therapeutic treatment are of virtually equal importance.
Care and preventive protection by a cosmetic treatment can be achieved in particular by application and introduction of active compounds, nutrients and/or care substances, but also by assisting or improving the physical and mechanical protection and/or barrier properties, such as elasticity, smoothness/roughness, dryness or biochemical equilibrium, of the skin. In particular, assisting, protecting, regulating and improving the moisture and fat content, in particular the so-called “natural moisturizing factor” (NMF) and the barrier function, of the skin represent an important treatment element here.
In the event of injury to or impairment of the skin or one of its central functions, treatment which is accompanied by an alleviating, healing or restoring action is of particular importance. Such a therapeutic treatment can likewise be effected by supplying particular active substances, healing substances or active compounds having a positive action, or by suitable assisting physical or biochemical methods which assist and favourably influence self-healing. The nature and scope of such a therapeutic treatment in this context depends in particular on the nature of the injury or dysfunction and is to be matched specifically to the affected layers of skin. In the field of wound care, so-called wound exudate management, wound debridement or influencing and regulation of the wound climate are to be mentioned here in particular.
For both fields, care cosmetics and the therapeutic field of skin treatment, the use of solid, dry, absorbent or hydratable formulation forms, in particular in the form of planar sheets, coverings or masks, is particularly suitable in principle and is also already widespread. In this context, those formulations which, in addition to the application of active compounds, also in themselves already have a skin-hydrating action are of interest in particular. This is equally relevant to cosmetic and to therapeutic skin treatment.
In particular, formulations based on hydrophilic, swellable hydrocolloids or polymers are known and used for this purpose. From the therapeutic field of wound treatment specifically, hydrogels in particular are known as wound treatment agents. In this context, hydrogels are distinguished in particular by a high water content or a high liquid uptake and storage capacity, as a result of which they are particularly suitable in particular for moist wound treatment. Hydrogels based on polyacrylates and their derivatives and those based on polyacrylic acids and salts thereof are particularly suitable compositions. In particular, synthetic acrylic acid polymers of the so-called “carbomers” groups are distinguished by a particularly good water uptake capacity. In this context, according to the USP-NF, British Pharmacopoeia, United States Adopted Names council (USAN) and Cosmetic Toiletries and Fragrance Association (CTFA), the term “carbomers” describes the group of Carbopols. Carbomers are also known by the term “superabsorbers”.
Those substances which are capable of taking up several times their own weight—up to 1,000 times—of liquids (usually water or distilled water) are called “superabsorbers” (also: superabsorbent polymers). In chemical terms, the carbomers are complex copolymers of acrylic acid and sodium acrylate, optionally additional crosslinking agents and/or acrylic acid derivatives, it being possible for the chemical composition of carbomers to vary.
Polyacrylates, their derivatives or also carbomers, and superabsorbers have a broad use spectrum both in the cosmetic and in the medical field of use. In cosmetics, carbomers or superabsorbers are employed as viscosity-increasing components in creams and lotions, as described, for example, in DE 10195737. By increasing the viscosity in the end product, they counteract a phase separation of the lipophilic and hydrophilic phase additionally to the emulsifiers, lead to a rich texture and contribute inter alia towards a pleasant sensation on the skin after application. Pure hydrogel products with a viscosity component based only on polyacrylate, which contain no or hardly any oils and only small amount of emulsifiers, acquire their phase stability chiefly via the viscosity of the polyacrylates contained therein.
On the basis of the capacity of polyacrylates, in addition to their good viscosity-increasing properties, also of taking up extreme amounts of aqueous liquids and of storing and holding these with extreme swelling, they are employed in particular in the therapeutic field of wound care, in particular in medical products for exudate management. The polyacrylate is usually employed here in the dry state as a powder or granules.
The preparation of micro- or nanoparticles or granular materials from polyacrylic acid polymers is also known, such particles usually being prepared from mixtures of the polyacrylic acid with further stabilizing natural or semisynthetic polymers. Thus, WO 00/22083 describes nanoporous granular materials based on acrylic acid/carboxymethylcellulose solutions, and WO 05/123034 describes microparticulate systems for example based on mixtures of polymethacrylate and sodium alginate solutions, which are in each case obtained by spray misting and freeze drying the polyacrylate-polymer mixtures.
The use of polyacrylic acid polymers for the preparation of microgel particles and the use thereof for encapsulation of active compounds, for example in the form of a microgel particle suspension applied to a wound covering of oxidized cotton, is known from GB 2431104.
Wound coverings based on polyacrylic acid polymers are moreover often combined with active compounds which are said to have a positive influence on wound healing. Thus e.g. a combination with fibronectin is described in WO 01/13967 or a combination with fibrillar collagen is described in GB 2080814 or a combination with growth factors, such as VEGF and PDGF, is described in WO 08/070,270.
In addition e.g. WO 07/122,232 discloses freeze-dried compositions for wound treatment which are obtainable by extrusion or electrospinning processes from mixtures of gelatine with polyacrylic acids.
Hydrogels with polyacrylate constituents and acrylates are moreover employed as glues or adhesives in the field of therapeutic wound care agents.
Both in cosmetic and in therapeutic skin treatment, however, those formulations which, in addition to a high wetting speed and a high water uptake and retention capacity, additionally have a good moistening and skin-hydrating action, that is to say also a good water-releasing capacity, are preferably also desirable. The hydrating action in cosmetic skin treatment plays an essential role in improving the mechanical and physical nature of the skin, e.g. with respect to elasticity and suppleness. In the field of wound treatment, if employed in dry wounds a hydrating action is of importance for improving and adjusting the wound climate and therefore for assisting the healing conditions in the wound. A suitable possibility for combining liquid uptake or absorption with hydration or moistening comprises combining those components which can meet both requirements in one composition. Mixtures of polyacrylates with a high water uptake and retention capacity and hydrocolloids, such as e.g. natural polymers, such as polysaccharides, in particular alginates, hyaluronic acid, carrageens or celluloses, with good hydrating properties are suitable in particular for this.
It is furthermore desirable in cosmetic use in particular, but also in external therapeutic use, to provide a composition which is configured to a certain extent as a leave-on product. For this, the product must be configured such that it can remain on the skin or in the hair practically completely and virtually without residue. Such leave-on products must furthermore have a certain viscosity, to be able to provide the user with a substantial formulation which is easy to apply. Efforts are therefore made to provide compositions which, with little filler or auxiliary substance material, but ideally high active compound contents, nevertheless have a high use viscosity.
Polymers based on polyacrylic acids and salts thereof, in particular so-called superabsorbers or also hydrogels, are suitable in particular for these purposes.
Water-containing hydrogels for wound care are often also on offer as amorphous gels in tubes or syringes. Such gel-like hydrogels are known, for example, from EP 583170, based on pure synthetic polymers, such as e.g. polyacrylate, or based on pure natural structured polymers, such as from WO 97/03710.
Gel-like mixtures of synthetic and natural structured polymers are also disclosed in the prior art, such as e.g. in EP 737703, the subject matter of which is liquid or amorphous polymeric hydrogels from polyester copolymers stabilized with polysaccharides, or from EP 1779836, which discloses hydrodispersions based on mixtures of polyacrylates and hydroxypropyl-guar.
DE 102005035879 discloses an aqueous hydrogel for wound care which, in addition to a synthetic acrylic acid derivative with a high water uptake capacity, contains at least one gel-forming polysaccharide and an electrolyte mixture of at least two different electrolytes. This hydrogel has a water content of at least 50 wt. % and has, according to the disclosure, particularly good absorbing and at the same time hydrating properties with a good modelling capacity and gel dimensional stability.
A disadvantage of such liquid, semi-liquid or gel-like application forms is in principle the high susceptibility to decay and microbial attack, which necessitates preservative measures. In this context, the addition of chemical preservatives in particular is rather undesirable. Physical preservative methods, such as irradiation or heat treatment, have a direct action on the structure of the gel-forming agents and therefore on the viscosity of the composition. These methods often lead to viscosity changes which can be adjusted only with difficulty and are uncontrollable.
Formulations in gel, powder or granule form furthermore as a rule are difficult to apply in and on the wound due to their non-cohesive, unshaped, dimensionally unstable state. Such non-cohesive compositions are also difficult to dose by amount. Furthermore, uniform distribution of the pulverulent/gel-like formulations is a problem.
Those application forms which have a solid, cohesive form and can be matched and adapted well in the configuration of their shape and size to the treatment parts to which they are to be applied are therefore preferably employed. In this context, formulations which are intended for treatments of the skin preferably have a planar configuration which makes simple and uniform application possible. In this context, suitable formulations should moreover have a certain dimensional stability and a mechanical cohesion, so that in addition to first being simple to apply, a further capacity for modelling on or in the treatment area is ideally also possible. It is moreover desirable to provide such planar, dry formulations in a shape and size adapted to the area to be treated, for which a certain mechanical stability of the formulations is likewise necessary.
In order to be able to provide such hydrogels or hydratable, swellable hydrocolloid compositions in a coherent, planar form with the desired properties with respect to preservative treatment, ease of application, dimensional stability and capacity for modelling, these are often offered in a dried form, e.g. in the form of films, sheets, pads or compresses. Dry formulations are also advantageous over water-containing or moist formulations with respect to storage and transportation.
In order to be able to bring hydrocolloids or hydrogel components, in particular polyacrylate gels, into a planar form, e.g. sheet or covering form, a certain mechanical stabilization of the dried hydrogel composition is necessary, since otherwise the material easily disintegrates into granules or powder after drying, e.g. during mechanical reworking, such as cutting into the desired shape, or also already during handling, in particular of dried compositions of large area.
Such dried hydrogel or polymer formulations which, by application to a solid, preferably textile and/or insoluble carrier, are stabilized mechanically and brought into a planar form which can be applied are known from the prior art.
Thus, WO 01/82886 describes a freeze-dried cosmetic “patch” of a rehydratable hydrocolloid composition which can contain natural polysaccharides, such as alginates, semisynthetic hydrocolloids, such as celluloses, or also synthetic polymers, such as polyacrylates, and which is obtainable by application of the hydrocolloid composition to a solid carrier adhering thereto, e.g. in the form of a nonwoven, a network or a crosslinked foam, e.g. of polyurethane, and subsequent freeze drying. The adhering carrier here is decisive for obtaining an adequate mechanical stability during the freeze drying process and during the later handling and application of the “patches”, and makes it first possible to provide the composition in the desired “patch” or mask form. In the processing of polyacrylic acid polymers in the cosmetics industry, the pH is generally neutralized, hence also in the process of the compositions described, which are neutralized by means of sodium hydroxide. This leads to the lack of stability of such compositions in the freeze drying and later handling, which is why application to an insoluble, stabilizing carrier is necessary.
Further dry hydrocolloid or hydrogel compositions in the form of planar sheets or masks which are stabilized by application of the hydrocolloid composition to a solid carrier are known from WO 99/20318 and WO 97/41900, wherein water-soluble hydrocolloid compositions, e.g. based on alginates, are applied to a solid substrate by pouring and are additionally stabilized on this by crosslinking with metal ions, before the formulations are subjected to a freeze drying.
The masks or patches from a mixture of synthetic structured polymers, such as e.g. polyacrylate, and natural hydrocolloids, such as e.g. alginate or cellulose, which are disclosed in DE 60113937 (arising from the abovementioned WO 01/82886), are stabilized by application to a solid fibrous carrier matrix such that the formulations freeze-dried on the carrier can be cut out into the desired shape.
Disadvantages of such formulations fixed to a carrier are the inhomogeneity of the material and, in particular, the need for removal of the insoluble, usually synthetic carrier matrix from or out of the part of the body or also wound to be treated. In particular, when hydrocolloid compositions which can be rehydrated to a gel are used in wound treatment, insoluble or non-rehydratable constituents in the composition are undesirable, since, for example, these are not absorbed or can be flushed out of the wound with the wound exudate only with difficulty. In a cosmetic treatment using a hydrogel composition which can be rehydrated to a viscous gel also, an insoluble carrier matrix is undesirable, since such a carrier layer impedes the incorporation of the active compounds and active substances contained in the composition, in particular e.g. by massage of the hydrated gel composition on the skin. It is also difficult for the hydrogel composition relevant for the treatment to be separated again from the carrier matrix, which as a rule is not relevant for the actual treatment, during use. In this context, on removal of the carrier matrix, a certain amount of hydrogel composition adhering to this or embedded in this is always also removed, which is then no longer available for the actual treatment. As a result, on the one hand a reproducible and accurately dosed application of the treatment agent or of active compounds is not possible, and on the other hand material resources are squandered unused by this means, which is also undesirable from economic aspects.
The provision of mechanically stable, dried hydrocolloid compositions, in particular in a planar configuration, which are stabilized without using such insoluble, planar-cohesive carrier materials is known, for example, from DE 4328329 or WO 01/78692, wherein membranes or masks based on freeze-dried natural structured polymers, for example based on sodium alginates, are disclosed. In this context, the matrices of DE 4328329 are stabilized by the addition of loose spun fibres, such as e.g. textile rayon fibres, or by a calcium crosslinking, such that the cast and freeze-dried blocks can be cut out into the desired mask shape. The freeze-dried gel matrices according to WO 01/78692 are likewise stabilized mechanically by partial crosslinking, in particular by calcium ions. In this context, however, neither document discloses mixtures of natural hydrocolloids with synthetic structured polymers, such as, in particular, those based on polyacrylate and its derivatives.
The documents WO 95/19795 or GB 2401879 also merely disclose dry sheet- or dry sponge-like hydrogel formulations which acquire stabilization by the addition of textile fibres, e.g. of rayon (viscose) or cotton, or of non-swelling synthetic polymer fibres, e.g. based on polyamide, polyester or polyether.
WO 03/051412, in contrast, discloses freeze-dried adsorbent sponge materials, for example in the form of uniform sheets, which are obtainable from synthetic polyacrylic acid polymers and are likewise stabilized with such insoluble, synthetic textile fibre materials, such as, in particular, with carboxymethylcellulose fibres.
The addition of insoluble textile fibres or other non-swelling synthetic fibre constituents to such rehydratable hydrogel formulations, which are soluble by gel formation, for stabilization is undesirable inasmuch as in the rehydrated gel these insoluble textile and non-swelling fibre constituents form an insoluble component which, especially in a cosmetic treatment, requires an expensive and undesirable removal by cleansing after the actual treatment. Such insoluble and non-swellable constituents also are not absorbable or degradable e.g. in a wound, and as particulate foreign bodies in a wound are potential triggers of granulation foci caused by encapsulation processes. Such granulation foci moreover represent a potential risk of infection, which is undesirable in particular in wounds which per se already heal poorly or chronic wounds with generally very unstable wound medium conditions. The particulate foreign bodies must usually be removed from the wound in an involved manner by rinsing.
In the case of stabilization by chemical crosslinking of the composition, the soluble polymer constituents are in principle converted into a water-insoluble composition which is irreversibly firmly bonded under conventional use conditions, as a result of which provision of dry hydrocolloid compositions, in particular in a planar sheet, foam or sponge configuration becomes possible.
Formulations stabilized in this way by crosslinking are also known from, in addition to the DE 4328329, WO 01/78692, WO 99/20318 or WO 97/41900 already cited, for example WO 97/39781 and WO 96/13285, wherein freeze-dried sponges and foams which are stabilized by crosslinking, have a high absorption capacity and are based on natural hydrocolloids are disclosed for wound treatment. Freeze-dried compositions from mixtures of at least one polymer based on polyacrylic acids and salts thereof with at least one natural polymer, such as, in particular, alginates, hyaluronic acid, carrageen or celluloses, which are in the form of a homogeneous, mechanically stable, but in this context carrier- or fibre-free matrix are also not disclosed here.
In contrast, such mixtures are in principle the subject matter of WO 03/068843, wherein so-called interpolyelectrolyte complexes of ionically crosslinked mixtures of polyacrylic acid polymers with chitosans, which belong to the group of natural polymers, are obtained. The gels obtainable via these can also be lyophilized, the configuration in the form of cohesive matrices or coverings not being described. Rather, the dried gels are ground to give a particulate material. An inadequate stability for provision in the form of cohesive sheets can be concluded from this.
Such mixtures are furthermore also known from DE 19710369, which discloses water-insoluble, chemically crosslinked nonwovens or masks for cosmetic use based on chitosan and derivatives, which are crosslinked with crosslinking agents such as, in particular, polyacrylic acids. The adequate stability for provision in the form of masks or nonwovens is achieved here by the chemical crosslinking of the polyacrylate polymer with the natural polymer chitosan, which belongs to the group of cationic polymers, whereas mixtures of polyacrylate/polyacrylate derivatives with so-called anionic natural polymers, such as e.g. alginates, hyaluronic acid, carrageen and/or with celluloses, also are not the subject matter of the disclosure content here.
Stabilizations obtained by crosslinking reactions cannot be rehydrated or can be rehydrated only with great difficulty, with dissociation and gel formation, to thus form soluble compositions. Partial crosslinkings to obtain rehydratable gel compounds, as described in WO 01/78692 or in WO 03/068843, are not suitable for obtaining adequate stabilization to provide mechanically stable, cuttable compositions, especially in the case of hydrogels based on mixtures of polyacrylate/polyacrylate derivatives and natural hydrocolloids. In addition, the dissolving of such a chemical crosslinking requires the addition of specific chemical reagents in the hydration liquid, which on the one hand severely impairs the flexibility in the choice of the composition of such liquids, and moreover is undesirable due to possible potential incompatibilities of such chemical additions.
The object of the present invention was therefore to provide a freeze-dried composition which has a high moisture uptake and retention capacity and in this context nevertheless also has a hydrating, that is to say moistening action and which can be provided in the form of a planar configuration, e.g. in the form of masks, coverings, sheets or pads, and in the form of shaped bodies of large format. This composition should moreover be rehydratable under the addition of hydrophilic liquids to form a homogeneous, finely disperse gel which is substantially free from macroscopic particles or fibre constituents, in order to be suitable in particular for cosmetic and therapeutic skin treatment.
By the combination of natural structure-forming polymers, such as, in particular, those from the group of anionic polymers, in particular from the group of polysaccharides, such as e.g. alginates, with at least one polymer based on polyacrylic acids and salts thereof, such as e.g. in particular those from the group of carbomers, sponge-like compositions or shaped bodies which have an adequate mechanical stability and which can be converted into application forms such as those in the form of masks, sheets, coverings or pads by cutting out can be prepared by freeze drying. Such freeze-dried compositions according to the invention are rehydratable without residue to the greatest extent and rapidly, with gel formation, and have a high moisture uptake and retention capacity and a good hydrating or moistening action.
Freeze-dried compositions which comprise synthetic polyacrylic acid polymers in combination with a natural polymer from the group of alginates are known, for example, from WO 99/65538 and WO 01/28600. In these, wound coverings which, in addition to the abovementioned polymeric hydrocolloids, moreover contain iodine-containing active compounds are described in these. The compositions of WO 99/65538 moreover are preferably prepared at a pH of 3-6.5.
Freeze-dried compositions in the form of a cohesive, sponge-like sheet material containing synthetic polyacrylic acid polymers in combination with a natural polymer from the group of hyaluronic acid and its derivatives are furthermore known, for example, from WO 94/01468, a neutralization with inorganic bases and no working at acid pH values being described herein.